Abstract In excitable cells, voltage-gated Na+ channels initiate the action potential. In recent years, it has been discovered that these channels are composed of many parts to form a macromolecular signaling complex. These different parts precisely tune the function of Na+ channels to the cells that they reside in. This proposal aims to begin to discover mechanisms of how one component, the ?-subunits, modulate the function and pharmacology of Na+ channels. If the proposed aims succeed, this new understanding could provide a route to more effective and precisely-directed therapies for excitability disorders such as arrhythmia and epilepsy.